Functional Optic Tract Rewiring Via Subtype- and Target-specific Axonal Regeneration and Presynaptic Activity Enhancement

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Mar 4

PMID 40038284

Authors

Xin Zhang

Chao Yang

Chengle Zhang

Junqiang Wu

Xiang Zhang

Jiayang Gao

Xuejie Wang

Leung Ting Chan

Yiren Zhou

Yujun Chen

Sindy Sing Ting Tam

Shuhang Chen

Yuqian Ma

Wing-Ho Yung

Liting Duan

Liwen Jiang

Yiwen Wang

Kai Liu

Affiliations

Soon will be listed here.

Abstract

Mechanisms underlying functional axonal rewiring after adult mammalian central nervous system (CNS) injuries remain unclear partially due to limited models. Here we develop a mouse intracranial pre-olivary pretectal nucleus (OPN) optic tract injury model and demonstrate that Pten/Socs3 knockout and CNTF expression in retinal ganglion cells (RGCs) promotes optic tract regeneration and OPN reinnervation. Revealed by transmission electron microscopy, trans-synaptic labeling, and electrophysiology, functional synapses are formed in OPN mainly by intrinsically photosensitive RGCs, thereby partially restoring the pupillary light reflex (PLR). Moreover, combining with Lipin1 knockdown accelerates the recovery and achieves functional reconnection after chronic injury. PLR can be further boosted by increasing RGC photosensitivity with melanopsin overexpression, and it can also be enhanced by treatment of a voltage-gated calcium channel modulator to augment presynaptic release. These findings highlight the importance of neuronal types and presynaptic activity for functional reconnection after CNS injuries.

References

Varadarajan S, Wang F, Dhande O, Le P, Duan X, Huberman A . Postsynaptic neuronal activity promotes regeneration of retinal axons. Cell Rep. 2023; 42(5):112476. PMC: 10247459. DOI: 10.1016/j.celrep.2023.112476. View

Han G, Wu W, Carman G . The Saccharomyces cerevisiae Lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme. J Biol Chem. 2006; 281(14):9210-8. PMC: 1424669. DOI: 10.1074/jbc.M600425200. View

Yu F, Haynes S, Teo G, Avtonomov D, Polasky D, Nesvizhskii A . Fast Quantitative Analysis of timsTOF PASEF Data with MSFragger and IonQuant. Mol Cell Proteomics. 2020; 19(9):1575-1585. PMC: 7996969. DOI: 10.1074/mcp.TIR120.002048. View

Tedeschi A, Bradke F . Spatial and temporal arrangement of neuronal intrinsic and extrinsic mechanisms controlling axon regeneration. Curr Opin Neurobiol. 2017; 42:118-127. DOI: 10.1016/j.conb.2016.12.005. View

Harel N, Strittmatter S . Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury?. Nat Rev Neurosci. 2006; 7(8):603-16. PMC: 2288666. DOI: 10.1038/nrn1957. View

Veiga Leprevost F, Haynes S, Avtonomov D, Chang H, Shanmugam A, Mellacheruvu D . Philosopher: a versatile toolkit for shotgun proteomics data analysis. Nat Methods. 2020; 17(9):869-870. PMC: 7509848. DOI: 10.1038/s41592-020-0912-y. View

Kelly E, Russo A, Jackson C, Lamantia C, Majewska A . Proteolytic regulation of synaptic plasticity in the mouse primary visual cortex: analysis of matrix metalloproteinase 9 deficient mice. Front Cell Neurosci. 2015; 9:369. PMC: 4585116. DOI: 10.3389/fncel.2015.00369. View

Kong A, Leprevost F, Avtonomov D, Mellacheruvu D, Nesvizhskii A . MSFragger: ultrafast and comprehensive peptide identification in mass spectrometry-based proteomics. Nat Methods. 2017; 14(5):513-520. PMC: 5409104. DOI: 10.1038/nmeth.4256. View

Petros T, Rebsam A, Mason C . Retinal axon growth at the optic chiasm: to cross or not to cross. Annu Rev Neurosci. 2008; 31:295-315. DOI: 10.1146/annurev.neuro.31.060407.125609. View

10.

Watkins T, Wang B, Huntwork-Rodriguez S, Yang J, Jiang Z, Eastham-Anderson J . DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. Proc Natl Acad Sci U S A. 2013; 110(10):4039-44. PMC: 3593899. DOI: 10.1073/pnas.1211074110. View

11.

Ylera B, Erturk A, Hellal F, Nadrigny F, Hurtado A, Tahirovic S . Chronically CNS-injured adult sensory neurons gain regenerative competence upon a lesion of their peripheral axon. Curr Biol. 2009; 19(11):930-6. DOI: 10.1016/j.cub.2009.04.017. View

12.

Benowitz L, He Z, Goldberg J . Reaching the brain: Advances in optic nerve regeneration. Exp Neurol. 2016; 287(Pt 3):365-373. DOI: 10.1016/j.expneurol.2015.12.015. View

13.

Young M, Lund R . The anatomical substrates subserving the pupillary light reflex in rats: origin of the consensual pupillary response. Neuroscience. 1994; 62(2):481-96. DOI: 10.1016/0306-4522(94)90381-6. View

14.

Kozicz T, Bittencourt J, May P, Reiner A, Gamlin P, Palkovits M . The Edinger-Westphal nucleus: a historical, structural, and functional perspective on a dichotomous terminology. J Comp Neurol. 2011; 519(8):1413-34. PMC: 3675228. DOI: 10.1002/cne.22580. View

15.

Picelli S, Faridani O, Bjorklund A, Winberg G, Sagasser S, Sandberg R . Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc. 2014; 9(1):171-81. DOI: 10.1038/nprot.2014.006. View

16.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

17.

Prichard J, Stoffel R, Quimby D, Obermeyer W, Benca R, Behan M . Fos immunoreactivity in rat subcortical visual shell in response to illuminance changes. Neuroscience. 2002; 114(3):781-93. DOI: 10.1016/s0306-4522(02)00293-2. View

18.

Tejero R, Balk S, Franco-Espin J, Ojeda J, Hennlein L, Drexl H . R-Roscovitine Improves Motoneuron Function in Mouse Models for Spinal Muscular Atrophy. iScience. 2020; 23(2):100826. PMC: 6992996. DOI: 10.1016/j.isci.2020.100826. View

19.

Courtine G, Gerasimenko Y, van den Brand R, Yew A, Musienko P, Zhong H . Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nat Neurosci. 2009; 12(10):1333-42. PMC: 2828944. DOI: 10.1038/nn.2401. View

20.

Williams P, Benowitz L, Goldberg J, He Z . Axon Regeneration in the Mammalian Optic Nerve. Annu Rev Vis Sci. 2020; 6:195-213. DOI: 10.1146/annurev-vision-022720-094953. View